Process for the preparation of N,N-substituted 5-amino-1,3-benzenedicarboxamides

ABSTRACT

The invention relates to a process for the preparation of a compound of formula (I), wherein R represents a 2,3-dihydroxy-1-propyl or a 1,3-dihydroxy-2-propyl radical, via direct amidation of a dialkyl ester of 5-amino-1,3-benzenedicarboxylic acid of formula (V), wherein R 1  represents a straight or branched (C 1 -C 4 )-alkyl group, with at least the stoichiometric amount of an amine of formula H 2 NR.

This application is the national stage filing of correspondinginternational application number PCT/EP01/13879, filed Nov. 28, 2001,which claims priority of Italian application MI2000A002600, filed Dec.1, 2000.

The present invention relates to a new process for the preparation ofN,N′-substituted 5-amino-1,3-benzenedicarboxamides of formula (I),

wherein R represents a 2,3-dihydroxy-1-propyl or a1,3-dihydroxy-2-propyl group.

Compounds (I) are useful as intermediates in the preparation of X-rayscontrast agents such as iopamidol (R=—CH(CH₂OH)₂) and iohexol orioversol (R=—CH₂—CH(OH)—CH₂OH).

BACKGROUND OF THE INVENTION

Compounds (I) above are known as key intermediates in the synthesis ofiodinated contrast agents.

U.S. Pat. No. 4,001,323 for instance describes a process for thepreparation of iopamidol (II)

by iodination of a compound (I) wherein R is a group —CH(CH₂OH)₂,followed by acylation of the 5-amino group by a suitably selected chiralacylating agent.

U.S. Pat. No. 4,250,113 on the other hand discloses a similar processfor the preparation of iohexol (III),

by iodination of a compound (I) wherein R is —CH₂—CH(OH)—CH₂OH,acetylation of the 5-amino group, and N-alkylation of the resulting5-acetamido group to yield the compound (III).

In the literature the compounds of formula (I) above are preparedstarting from 5-nitro-1,3-benzenedicarboxylic acid dimethyl ester,

by amidation of the ester groups with 2-amino-1,3-dihydroxypropane (acompound of formula H₂N—CH(CH₂OH)₂ commonly known as serinol) or with1-amino-2,3-dihydroxypropane (of formula H₂N—CH₂—CHOH—CH₂OH commonlyknown as isoserinol), followed by reduction of the 5-nitro group of thethus obtained N,N′-bis-substituted 5-nitro-1,3-benzenedicarboxamides(IV),

wherein R is as defined above, to 5-amino to yield the desired products(I).

The amidation reaction in said processes is typically carried out withat least the stoichiometric amounts of serinol or isoserinol (i.e. atleast two moles of serinol or isoserinol per mol of5-nitro-1,3-benzenedicarboxylic acid dimethyl ester), in the presence ofa protic organic solvent, such as a lower alkanol, and at a temperatureof from about 65° C. to about 150° C.

The intermediate product (IV) is then isolated and hydrogenated in thepresence of a suitable hydrogenation catalyst, such as Pd/C to yield theproduct (I).

An improvement to the above general method has recently been described,in WO 00/29372. The method there described involves carrying out theamidation reaction on the 5-nitro-1,3-benzenedicarboxylic acid loweralkyl esters in an organic solvent, typically a lower aliphatic alcohol,in the presence of a strong basic catalyst and then, without isolatingthe intermediate N,N′-substituted-5-nitro-1,3-benzenedicarboxamide (IV),catalytically hydrogenating the reaction solution to get the desiredproduct (I). Also in this case the temperature reported for theamidation of the 5-nitro derivative is from about 65° C. to 150° C.,depending on the type of solvent employed.

It has however been found that the products obtained through amidationof the 5-nitro-1,3-benzenedicarboxylic acid alkyl esters with2-amino-1,3-dihydroxypropane or with 1-amino-2,3-dihydroxypropane, i.e.the compounds of formula (IV), are products that must be handled withgreat care, for their characteristic instability. Specific differentialscanning calorimetry (DSC) tests have in fact demonstrated that thesecompounds are not stable at high temperatures even if maintained insolution. More particularly said DSC tests have shown that brought at atemperature of 120° C. the compounds of formula (IV) start decomposingwith the emission of fumes. The poor stability of the 5-nitro1,3-benzenedicarboxamides (IV) at high temperatures may drasticallylimit the choice of the reaction conditions that need to be strictlycontrolled particularly on industrial scale to prevent possible safetyand pollution problems. It may also negatively affect the yieldstheoretically obtainable in the overall process.

There is therefore a need for an improved process that might allow toobtain the intermediate compounds (I) with high yields under reactionconditions that are easily applicable in an industrial process and whereno stability problems may arise.

The process according to the present invention meets said need.

It has been found, in fact, that it is possible to obtain a compound offormula (I) in high yields also by direct amidation of a dialkyl esterof 5-amino-1,3-benzenedicarboxylic acid and that no stability problemsdo arise in connection with the dialkyl ester of5-amino-1,3-benzenedicarboxylic acid or with the5-amino-N,N′-bis-substituted-1,3-benzenecarboxamides (I) thus allowingthe reaction to be carried out industrially under widely varyingconditions.

SUMMARY OF THE INVENTION

A first object of the present invention is therefore a process for thepreparation of a compound of formula (I),

wherein R represents a 2,3-dihydroxy-1-propyl or a1,3-dihydroxy-2-propyl radical, via direct amidation of a dialkyl esterof 5-amino-1,3-benzenedicarboxylic acid of formula (V),

wherein R₁ represents a straight or branched (C₁-C₄)-alkyl group, withan at least stoichiometric amount of an amine of formula H₂NR wherein Ris as defined above.

Preferably, R₁ is selected from the straight (C₁-C₄)-alkyl groups, i.e.methyl, ethyl, n-propyl, and n-butyl. In a most preferred embodiment R₁represents a n-butyl group. While the two R₁ groups are generallyidentical, as the starting compounds of formula (V) where both R₁ havethe same meaning are more easily available, in principle they might alsobe different, e.g. each one may be independently selected from the groupof straight or branched (C₁-C₄)-alkyls.

The amidation reaction according to the present invention can be carriedout either in the presence of an organic solvent or in the absence of anorganic solvent, i.e. as a mass reaction in the molten state using theexcess of 2-amino-1,3-dihydroxypropane or 1-amino-2,3-dihydroxypropanein the molten state as the reaction medium.

When the reaction is carried out in the absence of a separate organicsolvent, the excess of 2-amino-1,3-dihydroxypropane or1-amino-2,3-dihydroxypropane is typically of at least 50% with respectto the stoichiometric amount and the reaction is carried out at atemperature above the melting temperature of2-amino-1,3-dihydroxypropane or 1-amino-2,3-dihydroxy-propane,respectively. Typically the reaction in such a case is carried out at atemperature over 100° C., generally at a temperature of from 100° C. to150° C., preferably comprised between 100° C. and 130° C. No problems ofstability do arise as the compounds of formula (I) as well the starting5-amino-1,3-benzenedicarboxylic acid esters (V) proved to be perfectlystable at temperatures as high as 150° C.

If a separate organic solvent is used, this is generally selected fromC₁-C₆ straight or branched alkanols, C₁-C₄ straight or branchedalkoxy-C₂-C₄ straight or branched alkanols, C₁-C₄ straight or branchedalkyl ethers and dipolar aprotic organic solvents. Particularlypreferred organic solvents in this case are C₁-C₄ straight alkanols,e.g. methyl alcohol, ethyl alcohol, n-propyl alcohol, and n-butylalcohol, C₁-C₄ straight alkoxy-C₂-C₄ straight alkanols, e.g.2-methoxyethanol, 2-ethoxyethanol, and 3-methoxypropanol, C₁-C₄ straightor branched alkyl ethers, e.g. ethyl ether, propyl ether, and1,2-dimethoxyethane, N,N-dimethylacetamide, N,N-dimethylformamide,N-methyl-2-pyrrolidone, and the like solvents. The reaction is anywaypreferably carried out in the presence of at least a slight excess of1-amino-2,3-dihydroxypropane or 2-amino-1,3-dihydroxypropane, typicallyof from about 5 to about 20% by mol with respect to the stoichiometricamount.

In a most preferred embodiment said amidation reaction is carried out inthe presence of a strong basic catalyst such as an alkali metalalcoholate, typically an alkali metal C₁-C₄ straight or branchedaliphatic alcoholate such as sodium methylate, sodium ethylate,potassium tert-butylate, and the like basic catalysts. It has been shownin fact that unexpectedly no side reactions of the 5-amino group dooccur even in the presence of a strong basic catalyst and that theamidation reaction proceeds with almost quantitative yields.

The catalyst may be added as such to the reaction mixture or it can begenerated in situ, by the addition of the alkali metal to a reactionmixture where the suitably selected solvent is the corresponding alcohol(or by the addition of the alkali metal to the alcohol that will then beused as the reaction solvent). Other strong basic catalysts might beemployed, such as for instance sodium or potassium hydroxides, but thewater that would form in these cases should preferably be removed beforethe reaction, e.g. by azeotropic distillation, to avoid hydrolysis ofthe starting esters (V).

As indicated above, the reaction can be carried out at a temperature offrom about 65° C. to about 150° C. without any problem of stability ofthe starting materials or of the obtained products.

When the reaction is completed, generally within a few hours, e.g. 1 to4 hours, the desired product (I) can be isolated by conventionalcrystallization procedures and further processed according to any of themethods known in the literature that involve the use of such anintermediate to give the desired contrast agents, such as iopamidol,iohexol, ioversol or iomeprol.

On the other hand the excess of 1-amino-2,3-dihydroxypropane or2-amino-1,3-dihydroxypropane used in the amidation reaction may berecovered—if desired—from the mother liquors of the crystallisation ofthe desired products (I), by e.g. suitably concentrating them, passingsaid concentrate on a cationic exchange resin, and eluting the fixedproduct with an ammonia solution. Recovery from this solution andpurification of these products may then be carried out as described forinstance in U.S. Pat. No. 5,866,719 or U.S. Pat. No. 6,111,142.

The starting compounds of formula (V) may be commercially available orthey may be prepared by either reduction of the corresponding5-nitro-1,3-benzenedicarboxylic acid alkyl esters or esterification of5-amino-1,3-benzenedicarboxylic acid.

In one embodiment of the process according to the present invention thestarting compounds of formula (V) are prepared from the corresponding5-nitro-1,3,-benzenedicarboxylic acid diesters (VI),

wherein R₁ has the same meaning as above, by reduction of the 5-nitrogroup to amino.

Any of the methods known in the literature to reduce an aromatic nitrogroup to amino can be employed, for example chemical reduction withacids and metals, such as Zn, Sn or Fe in acidic conditions, orpreferably catalytic hydrogenation with molecular hydrogen and e.g. Pd,Pt, typically supported on carbon, or Ni Ramey as the hydrogenationcatalyst. A preferred catalyst is however Pd/C where Pd amounts to fromabout 5 to about 10% by weight of the catalyst. Catalytic hydrogenationis generally carried out at atmospheric pressure, and at a temperaturecomprised between about 15° C. and about 70° C. It is carried out in thepresence of an organic solvent, such as C₁-C₆ straight or branchedalkanols, C₁-C₄ straight or branched alkoxy-C₂-C₄ straight or branchedalkanols, C₁-C₄ straight or branched alkyl ethers, or any other inertorganic solvent. Optionally an amount of acid, such as hydrochloricacid, of from 0.1÷2 mol per mol of reactant can be present.

The completion time for this hydrogenation reaction is generallycomprised between 0.5 and 6 hours. At the end of the reaction thecatalyst is recovered by filtration and, if desired, it can be recycled.The reduced product of formula (V) can then be isolated from thefiltered solution by bringing the pH to a value of from about 7.5 toabout 10 and recovering the precipitate by filtration. It is however notnecessary to isolate the compound of formula (V) from the solution as itis possible to carry out the amidation reaction directly thereon. Insuch a case, if the amidation is carried out according to the preferredembodiment that involves the use of a strong basic catalyst and thecatalytic hydrogenation was carried out in acidic conditions, then itwill be necessary first to remove any water possibly present by e.g.azeotropic distillation and then employ a larger amount of the basiccatalyst as part of it will be used to neutralise the acid present inthe reaction mixture. If isolation of the compound of formula (V) is notcarried out, then the solvent employed for the catalytic hydrogenationreaction will be preferably a C₁-C₆ straight or branched alkanol, or aC₁-C₄ straight or branched alkoxy-C₂-C₄ straight or branched alkanol andeven more preferably a C₁-C₄ straight alkanol, or a C₁-C₄ straightalkoxy-C₂-C₄ straight alkanol.

In their turn the compounds of formula (VI) may be commerciallyavailable or can be easily prepared according to known methods, e.g. byesterification of the 5-nitro-1,3-benzenedicarboxylic acids.

In another embodiment of the present invention the starting compounds offormula (V) are prepared by esterification of5-amino-1,3-benzenedicarboxylic acid with the corresponding alcoholR¹OH, typically used as the reaction solvent, in the presence of anacidic catalyst, e.g. p-toluenesulphonic acid. The reaction quickly andeasily proceeds by removing the water that forms in the esterificationby e.g. azeotropic distillation. Also in this case it is not necessaryto isolate the compounds of formula (V) as the amidation reaction can becarried out directly on the reaction mixture by using a larger amount ofthe strong basic catalyst.

As indicated above the product of formula (I) obtained according to theclaimed process can then be further processed according to any of themethods known in the literature that involve use of such an intermediateto give the end desired contrast agents, such as iopamidol, iohexol,ioversol or iomeprol.

It is therefore a further specific object of the present invention aprocess for the manufacture of a product selected from the groupconsisting of iopamidol, iohexol, ioversol, and iomeprol involving theuse of a corresponding intermediate compound of formula (I), saidprocess being characterised in that the intermediate of formula (I) isobtained by direct amidation of a dialkyl ester of5-amino-1,3-benzenedicarboxylic acid of formula (V),

wherein R₁ represents a straight or branched (C₁-C₄)-alkyl group, withat least the stoichiometric amount of an amine of formula H₂NR wherein Ris a 1,3-dihydroxy-2-propyl or a 2,3-dihydroxy-1-propyl group.

A further specific object of the invention is, in particular, a processfor the preparation of iopamidol which comprises

-   -   manufacturing an intermediate of formula (I) wherein R is a        1,3-dihydroxy-2-propyl group by the new process of the present        invention;    -   suitably iodinating the benzene ring; and    -   introducing the (S)-2-(acetyloxy)propanoyl group on the 5-amino        group.

Another further specific object of the invention is, in particular, aprocess for the preparation of iohekol which comprises

-   -   manufacturing an intermediate of formula (I) wherein R is a        2,3-dihydroxy-1-propyl group by the new process of the present        invention;    -   suitably iodinating the benzene ring; and    -   N-acetylating and suitably N-alkylating the 5-amino group.

The following examples further illustrate the present invention but neednot to be viewed as a limitation to the scope thereof.

EXAMPLE 15-amino-N,N′-bis[2-hydroxy-1-(hydroxymethyl)ethyl]-1,3-benzenedicarboxamide

5-Amino-1,3-benzenedicarboxylic acid dimethyl ester (40.0 g, 191 mmol)and 2-amino-1,3-dihydroxypropane (104.5 g, 1.147 mol) are loaded into a1 L vessel equipped with a mechanical stirrer, a thermometer and arefluxing refrigerator. The suspension is heated up to 105° C., and ismaintained at this temperature for 150 minutes to yield a solution.After cooling to 50° C., methanol (0.7 L) is added and the obtainedsuspension is maintained for 4 hours at room temperature. The solid thatseparates is filtered, washed with methanol (0.3 L), and dried in theoven at 45° C. for 4 hours yielding the compound of the title (56.3 g,0.172 mol, yield: 90%).

EXAMPLE 25-amino-N,N′-bis[2-hydroxy-1-(hydroxymethyl)ethyl]-1,3-benzenedicarboxamide

2-Amino-1,3-dihydroxypropane (27.4 g, 300 mmol) and 1.5M solution ofsodium methylate in methanol (14.3 mL, 21.5 mmol) are added to asuspension of 5-amino-1,3-benzenedicarboxylic acid dimethyl ester (30.0g, 143 mmol) in methanol (0.2 L). The reaction mixture is heated to thereflux temperature to get a solution. After 2.5 hours of reflux and 4hours at room temperature the reaction mixture is filtered and the solidon filter is washed with methanol (40 mL) and dried yielding the productof the title (43.5 g, 133 mmol, yield: 93%).

EXAMPLE 35-amino-N,N′-bis[2-hydroxy-1-(hydroxymethyl)ethyl]-1,3-benzenedicarboxamide

A mixture of 2-amino-1,3-dihydroxypropane (31 g, 340 mmol) and5-amino-1,3-benzenedicarboxylic acid di-n-butyl ester (20.0 g, 68.2mmol) is heated to 125° C. for 3 hours while the n-butyl alcohol whichforms is distilled off. After cooling the reaction mixture to about 70°C. the solution is diluted with methanol (0.35 L) and a solid productcrystallizes out. After 4 hours at room temperature the mixture isfiltered and the solid on filter is washed with methanol (30 mL) anddried yielding the compound of the title (21.4 g, 65.5 mmol, yield:96%).

EXAMPLE 45-amino-N,N′-bis[2-hydroxy-1-(hydroxymethyl)ethyl]-1,3-benzenedicarboxamide

5-Amino-1,3-benzenedicarboxylic acid di-n-butyl ester (1148 g, 3.91 mol)is loaded into a 10 L reaction vessel containing methanol (7.5 L) and a1.5M solution of sodium methylate in methanol (0.39 L, 0.59 mol) and2-amino-1,3-dihydroxypropane (820 g, 9.0 mol) are added thereto. Thereaction mixture is then heated to the reflux temperature and kept atthis temperature for 4 hours. The mixture is then concentrated to 4 L,cooled to 25° C. and after one night at room temperature it is filtered.The solid on filter is washed with methanol (2×1.3 L) and dried yieldingthe compound of the title (1215 g, 3.71 mol, yield: 95%).

EXAMPLE 55-amino-N,N′-bis(2,3-dihydroxy-1-propyl)-1,3-benzenedicarboxamide

The compound of the title is obtained by following substantially thesame procedure as in the preceding example but using1-amino-2,3-dihydroxypropane instead of 2-amino-1,3-dihydroxypropane.

EXAMPLE 6 Preparation of the 5-amino-1,3-benzenedicarboxylic AcidDimethyl Ester

5-Nitro-1,3-benzenedicarboxylic acid dimethyl ester (95.7 g, 0.4 mol)and 5% Pd/C (8 g) are loaded into a 2 L hydrogenation vessel equippedwith a thermometer and a mechanical stirrer, that contains methanol (0.8L) and 2M HCl (0.3 L; 0.6 mol). The obtained suspension is maintainedunder mechanical stirring and purged with nitrogen washings, at the endof which the hydrogenation reaction is carried out at a temperaturecomprised between 45 and 55° C. The reaction is complete in 2 hours. Anitrogen flow is then passed through the reaction vessel to wash out anyhydrogen gas, the catalyst is filtered off and the obtained solution isevaporated under vacuum to yield a solid residue. The obtained productis loaded into a 5 L vessel, equipped with a mechanical stirrer, andcontaining deionized water (3 L) and 34% HCl (0.1 L). The obtainedsuspension is filtered from the insoluble residue and 2M NaOH is addedto the filtrate up to pH 10. The solid product that crystallizes out isrecovered by filtration, washed with deionized water and dried undervacuum in the presence of P₂O₅ yielding the compound of the title (77.0g; 0.368 mol, yield: 92%).

The ¹H-NMR, ¹³C-NMR, IR and MS are consistent with the indicatedstructure

EXAMPLE 7 Preparation of 5-amino-1,3-benzenedicarboxylic acid di-n-butylEster

A mixture of 5-amino-1,3-benzenedicarboxylic acid (632 g, 3.49 mol),n-butyl alcohol (7.5 L) and p-toluenesulphonic acid (860 g, 4.52 mol) isloaded into a 10 L reaction vessel and heated to 97° C. under stirringunder a reduced pressure of about 450 mBar removing the azeotropen-butyl alcohol/water that forms. After 11 hours of heating the reactionmixture is concentrated to 2.4 L, cooled to 60° C. and neutralised bythe addition of 5M NaOH (0.9 L). The mixture is further cooled to about10° C. and diluted with water 3.4 L). After 15 hours at room temperaturethe solid is recovered by filtration, washed with water (2×1 L) anddried yielding the 5-amino-1,3-benzenedicarboxylic acid di-n-butyl ester(930 g, 3.17 mol, yield: 91%).

EXAMPLE 8 Preparation of Iopamidol

a)5-amino-N,N′-bis[2-hydroxy-1-(hydroxymethyl)ethyl]-2,4,6-triiodo-1,3-benzenedicarboxamide

The compound of Example 1 (9.0 g, 27.5 mmol), deionized water (0.75 L)and 1M HCl (15 mL) are loaded into a 1 L vessel, equipped with amechanical stirrer and a thermometer. A solution of NaICl₂ (sol. at25.6% of iodine) (38.6 g, 0.078 mol) is added thereto in 15 minutes andthe obtained solution is maintained under stirring for 30 minutes atroom temperature and at 50° C. for 5 hours.

The solid product which precipitates is filtered, washed with a solutionof sodium bisulfite, then with deionized water and dried under vacuum ina oven yielding the5-amino-N,N′-bis[2-hydroxy-1-(hydroxymethyl)ethyl]-2,4,6-triiodo-1,3-benzenedicarboxamideintermediate (14.5 g, 20.6 mmol, yield: 75%).

The ¹H-NMR, ¹³C-NMR, IR and MS are consistent with the indicatedstructure.

b) Iopamidol

The5-amino-N,N′-bis[2-hydroxy-1-(hydroxymethyl)ethyl]-2,4,6-triiodo-1,3-benzenedicarboxamideintermediate product obtained by following the procedure of step a)above (21 g, 29.8 mmol) is added to N,N-dimethylacetamide (0.2 L) andanhydrous HCl (0.33 g; 9 mmol) is bubbled therein. The solution is thencooled to 15° C. and (S)-2-(acetyloxy)propanoyl chloride (31.4 g, 208mmol) is then dripped therein in two hours. The mixture is stirred for48 hours at 23° C., the solvent is partially evaporated and the residueis taken up with deionized water (0.2 L). The solution is warmed to thetemperature of 55° C. and kept at this temperature for 2 hours, tohydrolyse the obtained oxazolidine compounds having the structureindicated below.

After cooling to 40° C., 2M NaOH is added until the pH of the mixturereaches 10.5 and this pH value is maintained up to the completehydrolysis of the acetic group.

The reaction mixture cooled to 25° C., is then loaded into a system ofion exchange resin columns, cationic and anionic respectively. Theeluate is collected, and concentrated to a residue which is thencrystallized from ethanol. The solid is filtered, washed on filter withethanol and dried at a temperature of 45° C. for 5 hours in an ovenyielding the desired iopamidol (17.8 g, 22.9 mmol, yield: 77%).

The ¹H-NMR, ¹³C-NMR, IR and MS are consistent with the indicatedstructure.

EXAMPLE 9 Preparation of Iopamidol

Iopamidol can also be prepared by the above procedure where the firststep, the preparation of5-amino-N,N′-bis[2-hydroxy-1-(hydroxymethyl)ethyl]-2,4,6-triiodo-1,3-benzenedicarboxamideis carried out as follows:

The compound of Example 1 (671 g, 2.05 mol), is loaded into a 10 Lreaction vessel containing deionized water (9.2 L) and 96% H₂SO₄ (107 g)and the solution is heated to 70° C. ICl (a solution of 44% iodine in14.5% HCl) (1920 g, 6.65 mol) is gradually dripped in (about 1 hour) andthe reaction mixture is then maintained at about 70° C. for additional 9hours. After overnight at room temperature the solid is recovered byfiltration, washed on filter with water (2×0.6 L), and dried yieldingthe5-amino-N,N′-bis[2-hydroxy-1-(hydroxymethyl)ethyl]-2,4,6-triiodo-1,3-benzenedicarboxamide(1300 g, 1.85 mol, yield: 90%).

EXAMPLE 10 Preparation of Iohexol

a)5-(acetylamino)-N,N′-bis(2,3-dihydroxypropyl)-2,4,6-triiodo-1,3-benzenedicarboxamide

5-Amino-N,N′-bis[2,3-dihydroxypropyl]-1,3-benzenedicarboxamide (44 g, 62mmol) is suspended in acetic anhydride (210 mL) and concentratedsulphuric acid (1.5 mL) is added thereto. The reaction mixture is thenwarmed to 60° C. for 90 minutes, concentrated and the obtained residueis taken up with a mixture of methanol (120 mL) and deionized water (70mL) and heated to 50° C. while the pH is kept at 10.5 by sequentialadditions of NaOH.

Once the hydrolysis reaction is over, the solution is cooled to roomtemperature and neutralised with HCl.

The obtained solution is stirred at room temperature for 18 hours, thenthe solid that precipitates is recovered by filtration, washed withwater and dried yielding the intermediate5-(acetylamino)-N,N′-bis(2,3-dihydroxypropyl)-2,4,6-triiodo-1,3-benzenedicarboxamide(32.0 g, 43 mmol, yield: 69%).

b) Iohexol

A sample of the above prepared product (30 g, 40 mmol) is dissolved inpropylene glycol (100 mL) with the addition of 4M sodium methylate (15mL, 60 mmol) and brought at a temperature of 50° C. The obtainedsolution is partially concentrated and cooled to room temperature.1-Chloro-2,3-dihydroxypropane (5.0 mL, 60 mmol) is then added thereto,the reaction mixture is then maintained under stirring for 32 hours, andconcentrated under vacuum to a solid residue which is taken up withmethanol and filtered. The filtrate is concentrated to a residue, thatis dissolved in water and purified from salts by means of ionic exchangeresins. The deionized solution is concentrated to a residue and theobtained product is crystallized from butanol, thus yielding uponfiltration and drying the desired iohexol (19.7 g, 24 mmol, yield: 60%).

The ¹H-NMR, ¹³C-NMR, IR and MS are consistent with the indicatedstructure.

1. A process for the preparation of a compound of formula (I)

wherein R represents a 2,3-dihydroxy-1-propyl or a1,3-dihydroxy-2-propyl radical, which comprises reacting a di-alkylester of 5-amino-1,3-benzenedicarboxylic acid of formula (V),

wherein R₁ represents a straight or branched (C₁-C₄)-alkyl group, withat least two moles of an amine of formula H₂NR wherein R is as definedabove.
 2. The process of claim 1 wherein the starting compound offormula (V) is obtained by reduction of the corresponding5-nitro-1,3-benzenedicarboxylic acid di-alkyl esters of formula (VI),

wherein R₁ is as defined above.
 3. The process of claim 1 wherein thestarting compound of formula (V) is obtained by esterification of the5-amino-1,3-benzenedicarboxylic acid with an alcohol R¹OH.
 4. Theprocess of claim 1 wherein the reaction is carried out at a temperatureof from about 65° C. to about 150° C., using an excess of the amine RNH₂with respect to the stoichiometric amount required by the reaction,either in the presence of an organic solvent, selected from C₁-C₆straight or branched alkanols, C₁-C₄ straight or branched alkoxy-C₂-C₄straight or branched alkanols, C₁-C₄ straight or branched alkyl ethersand dipolar aprotic organic solvents or in the absence of a separateorganic solvent, using the excess of the amine in its molten state asthe reaction medium.
 5. The process of claim 4 wherein the reaction iscarried out in the presence of an organic solvent and of a strong basiccatalyst.
 6. The process of claim 5 wherein the-organic solvent isselected from C₁-C₄ straight or branched alkanols, and C₁-C₄ straightalkoxy-C₂-C₄ straight alkanols, and the strong basic catalyst is analkali metal C₁-C₄ straight or branched aliphatic alcoholate.
 7. Theprocess of claim 2 wherein the compound of formula (V) is not isolated.8. The process of claim 1 wherein R₁ is a n-butyl group.
 9. A processfor the manufacture of a product selected from the group consisting ofiopamidol, iohexol, ioversol, and iomeprol involving the use of acorresponding intermediate compound of formula (I), said process beingcharacterised in that the intermediate of formula (I) is obtained by theprocess of any of the preceding claims 1 to
 8. 10. A process for thepreparation of iopamidol which process comprises preparing manufacturingan intermediate of formula (I) wherein R is a 1,3-dihydroxy-2-propylgroup by the process of any of preceding claims 1 to 8; suitablyiodinating the benzene ring; and introducing the(S)-2-(acetyloxy)propanoyl group on the 5-amino group.
 11. A process forthe preparation of iohexol which process comprises preparing anintermediate of formula (I) wherein R is a 2,3-dihydroxy-1-propyl groupby the process of any of preceding claims 1 to 8; suitably iodinatingthe benzene ring; and N-acetylating and suitably N-alkylating the5-amino group.
 12. The process of claim 3 wherein the compound offormula (V) is not isolated.
 13. A process for the manufacture of aproduct selected from the group consisting of iopamidol, iohexol,ioversol, and iomeprol involving the use of a corresponding intermediatecompound of formula (I), said process being characterised in that theintermediate of formula (I) is obtained by the process of claim
 12. 14.A process for the preparation of iopamidol which process comprisespreparing manufacturing an intermediate of formula (I) wherein R is a1,3-dihydroxy-2-propyl group by the process of claim 12; suitablyiodinating the benzene ring; and introducing the(S)-2-(acetyloxy)propanoyl group on the 5-amino group.
 15. A process forthe preparation of iohexol which process comprises preparing anintermediate of formula (I) wherein R is a 2,3-dihydroxy-1-propyl groupby the process of claim 12; suitably iodinating the benzene ring; andN-acetylating and suitably N-alkylating the 5-amino group.